Farnesyl Protein transferase inhibitors with in vivo radiosensitizing properties

ABSTRACT

The present invention is concerned with the finding that farnesyl protein transferase inhibitors have radiosensitizing properties which makes them useful for preparing a pharmaceutical composition for administration before, during or after irradiation of a tumor for treating cancer in vivo.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage application under 35 U.S.C. §371of International Application No. PCT/EP99/04545 filed Jun. 30, 1999,which claims priority from EP 98202257.6, filed Jul. 6, 1998, and EP98204330.9, filed Dec. 18, 1998, the contents of all of which are herebyincorporated by reference.

The present invention is concerned with the finding that farnesylprotein transferase inhibitors have radiosensitizing properties whichmakes them useful for preparing a pharmaceutical composition foradministration before, during or after irradiation of a tumor fortreating cancer in vivo.

WO-97/21701 describes the preparation, formulation and pharmaceuticalproperties of farnesyl protein transferase inhibiting(imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II)and (III), as well as intermediates of formula (II) and (III) that aremetabolized in vivo to the compounds of formula (I). The compounds offormulas (I), (II) and (III) are represented by

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl,pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, aminoC₁₋₆alkyl,

or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or —Alk¹—S(O)₂—R⁹,wherein Alk¹ is C₁₋₆alkanediyl,

R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino orC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,4,4-dimethyloxazolyl; or

when on adjacent positions R² and R³ taken together may form a bivalentradical of formula

—O—CH₂—O—  (a-1),

—O—CH₂—CH₂—O—  (a-2),

—O—CH═CH—  (a-3),

—O—CH₂—CH₂—  (a-4),

—O—CH₂—CH₂—CH₂—  (a-S), or

—CH═CH—CH═CH—  (a-6);

R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R⁶ and R⁷ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,or

when on adjacent positions R⁶ and R⁷ taken together may form a bivalentradical of formula

—O—CH₂—O—  (c-1), or

—CH═CH—CH═CH—  (c-2);

R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1),

—S—R¹⁰  (b-2),

—N—R¹¹R¹²  (b-3),

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, anatural amino acid, Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

wherein Alk² is C₁₋₆alkanediyl;

 R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr²C₁₋₆alkyl;

 R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

 R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹or Ar²C₁₋₆alkyl;

R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹;

R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

R¹⁹ is hydrogen or C₁₋₆alkyl;

Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and

Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo.

WO-97/16443 concerns the preparation, formulation and pharmaceuticalproperties of farnesyl protein transferase inhibiting compounds offormula (IV), as well as intermediates of formula (V) and (VI) that aremetabolized in vivo to the compounds of formula (IV). The compounds offormulas (IV), (V) and (VI) are represented by

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl,pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, aminoC₁₋₆alkyl,

or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or —Alk¹—S(O)₂—R⁹,wherein Alk¹ is C₁₋₆alkanediyl,

R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino orC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

R² and R³ each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl; or

when on adjacent positions R² and R³ taken together may form a bivalentradical of formula

—O—CH₂—O—  (a-1),

—O—CH₂—CH₂—O—  (a-2),

—O—CH═CH—  (a-3),

—O—CH₂—CH₂—  (a-4),

—O—CH₂—CH₂—CH₂—  (a-5), or

—CH═CH—CH═CH—  (a-6);

R⁴ and R⁵ each independently are hydrogen, Ar¹, C₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R⁶ and R⁷ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy or Ar²oxy;

R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, Ar¹,Ar²C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl;

R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

R¹¹ is hydrogen or C₁₋₆alkyl;

Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo;

Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo.

PCT/EP98/01296, filed Mar. 3, 1998, concerns the preparation,formulation and pharmaceutical properties of farnesyl proteintransferase inhibiting compounds of formula (VII)

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

—A— is a bivalent radical of formula

—CH═CH—  (a-1),

—CH₂—CH₂—  (a-2),

—CH₂—CH₂—CH₂—  (a-3),

—CH₂—O—  (a-4),

—CH₂—CH₂—O—  (a-5),

—CH₂—S—  (a-6),

—CH₂—CH₂—S—  (a-7),

—CH═N—  (a-8),

—N═N—  (a-9), or

—CO—NH—  (a-10);

wherein optionally one hydrogen atom may be replaced by C₁₋₄alkyl orAr¹;

R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar²,Ar²—C₁₋₆alkyl, Ar²-oxy, Ar²—C₁₋₆alkyloxy;

or when on adjacent positions R¹ and R² taken together may form abivalent radical of formula

—O—CH₂—O—  (b-1),

—O—CH₂—CH₂—O—  (b-2),

—O—CH═CH—  (b-3),

—O—CH₂—CH₂—  (b-4),

—O—CH₂—CH₂—CH₂—  (b-5), or

—CH═CH—CH═CH—  (b-6);

R³ and R⁴ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar³-oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, trihalomethyl,trihalomethoxy, or

when on adjacent positions R³ and R⁴ taken together may form a bivalentradical of formula

—O—CH₂—O—  (C-1),

—O—CH₂—CH₂—O—  (c-2), or

—CH═CH—CH═CH—  (c-3);

R⁵ is a radical of formula

 wherein R¹³ is hydrogen, halo, Ar⁴, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;

R¹⁴ is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

R⁶ is hydrogen, hydroxy, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋ ₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar⁵,Ar⁵—C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

—O—R⁷  (e-1),

—S—R⁷  (e-2),

—N—R⁸R⁹  (e-3),

wherein R⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar⁶,Ar⁶—C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹⁰ or —Alk—NR¹¹R¹²;

R⁸ is hydrogen, C₁₋₆alkyl, Ar⁷ or Ar⁷—C₁₋₆alkyl;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar⁸, Ar⁸—C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,Ar⁸-carbonyl, Ar⁸—C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk—OR¹⁰ or—Alk—NR¹¹R¹²;

wherein Alk is C₁₋₆alkanediyl;

 R¹¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar⁹ orAr⁹—C₁₋₆alkyl;

 R¹¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹⁰ or Ar¹⁰—C₁₋₆alkyl;

 R¹² is hydrogen, C₁₋₆alkyl, Ar¹¹ or Ar¹¹—C₁₋₆alkyl; and

 Ar¹ to Ar¹¹ are each independently selected from phenyl; or phenylsubstituted with halo, C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl.

PCT/EP98/02357, filed Apr. 17, 1998, concerns the preparation,formulation and pharmaceutical properties of farnesyl proteintransferase inhibiting compounds of formula (VIII)

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar¹C₁₋₆alkyl, Ar¹oxy or Ar¹C₁₋₆alkyloxy;

R³ and R⁴ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar¹oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, trihalomethylor trihalomethoxy;

R⁵ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋ ₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

—O—R¹⁰  (a-1),

—S—R¹⁰  (a-2),

—N—R¹¹R¹²  (a-3),

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar¹C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;

R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar¹C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,Ar¹carbonyl, Ar¹C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵;

wherein Alk is C₁₋₆alkanediyl;

 R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr¹C₁₋₆alkyl;

 R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

 R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar¹C₁₋₆alkyl;

R⁶ is a radical of formula

wherein R¹⁶ is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R¹⁷ is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

R⁷ is hydrogen or C₁₋₆alkyl provided that the dotted line does notrepresent a bond;

R⁸ is hydrogen, C₁₋₆alkyl or Ar²CH₂ or Het¹CH₂;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; or

R⁸ and R⁹ taken together to form a bivalent radical of formula

—CH═CH—  (c-1),

—CH₂—CH₂—  (c-2),

—CH₂—CH₂—CH₂—  (c-3),

—CH₂—O—  (c-4), or

—CH₂—CH₂—O—  (c-5);

Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl;

Ar² is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl; and

Het¹ is pyridinyl; pyridinyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

Other useful farnesyl protein transferase inhibitors have the structure

These farnesyl protein transferase inhibitors decrease the growth oftumors in vivo by a direct effect on tumor cell growth but alsoindirectly, i.e. by inhibiting angiogenesis (Rak. J. et al, CancerResearch, 55, 4575-4580, 1995). Consequently, treatment with theseinhibitors suppresses solid tumor growth in vivo at least in part byinhibiting angiogenesis. This being the case, one could expect thattreatment with these compounds could result in hypoxic tumors, therebyinducing or causing increased radio-resistance.

Unexpectedly, we have now found that that does not happen. On thecontrary, it appears that administration of a farnesyl proteintransferase inhibitor as described hereinbefore sensitizes tumor cellsin vivo to irradiation or ionizing radiation and moreover, resensitizesradioresistant cells. Thus, farnesyl protein transferase inhibitors areuseful as in vivo radiosensitizing (radiation-sensitizing orradiation-potentiating) agents.

The present invention is concerned with the use of at least a farnesylprotein transferase inhibitor for the preparation of a pharmaceuticalcomposition having radiosensitizing properties for administrationbefore, during or after irradiation of a tumor for treating cancer invivo.

In particular, the present invention is concerned with the use of atleast a farnesyl protein transferase inhibitor for the preparation of apharmaceutical composition having radiosensitizing properties foradministration before, during or after irradiation of a tumor fortreating cancer in vivo, wherein said farnesyl protein transferaseinhibitor is an (imidazoly-5-yl)methyl-2-quinolinone derivative offormula (I), or a compound of formula (II) or (III) which is metabolizedin vivo to the compound of formula (I), said compounds being representedby

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl,pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, aminoC₁₋₆alkyl,

or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or —Alk¹—S(O)₂—R⁹,wherein Alk¹ is C₁₋₆alkanediyl,

R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino orC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,4,4-dimethyloxazolyl; or

when on adjacent positions R² and R³ taken together may form a bivalentradical of formula

—O—CH₂—O—  (a-1),

—O—CH₂—CH₂—O—  (a-2),

—O—CH═CH—  (a-3),

—O—CH₂—CH₂—  (a-4),

—O—CH₂—CH₂—CH₂—  (a-5), or

—CH═CH—CH═CH—  (a-6);

R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R⁶ and R⁷ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,or

when on adjacent positions R⁶ and R⁷ taken together may form a bivalentradical of formula

—O—CH₂—O—  (c-1), or

—CH═CH—CH═CH—  (c-2);

R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1),

—S—R¹⁰  (b-2),

—N—R¹¹R¹²  (b-3),

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, anatural amino acid, Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

wherein Alk² is C₁₋₆alkanediyl;

 R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr²C₁₋₆alkyl;

 R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

 R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹;

R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

R¹⁹ is hydrogen or C₁₋₆alkyl;

Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and

Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo.

In formulas (I), (II) and (III), R⁴ or R⁵ may also be bound to one ofthe nitrogen atoms in the imidazole ring. In that case the hydrogen onthe nitrogen is replaced by R⁴ or R⁵ and the meaning of R⁴ and R⁵ whenbound to the nitrogen is limited to hydrogen, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl, C₁₋₆alkylS(O)₂C₁₋₆alkyl.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₁₋₈alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 or 8 carbon atoms such as, forexample heptyl or octyl; C₁₋₁₂alkyl again encompasses C₁₋₈alkyl and thehigher homologues thereof containing 9 to 12 carbon atoms, such as, forexample, nonyl, decyl, undecyl, dodecyl; C₁₋₁₆alkyl again encompassesC₁₋₁₂alkyl and the higher homologues thereof containing 13 to 16 carbonatoms, such as, for example, tridecyl, tetradecyl, pentadecyl andhexadecyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refersto a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to asulfon. The term “natural amino acid” refers to a natural amino acidthat is bound via a covalent amide linkage formed by loss of a moleculeof water between the carboxyl group of the amino acid and the aminogroup of the remainder of the molecule. Examples of natural amino acidsare glycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine.

The pharmaceutically acceptable acid or base addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid and non-toxic base addition salt forms which the compounds offormulas (I), (II) and (III) are able to form. The compounds of formulas(I), (II) and (III) which have basic properties can be converted intheir pharmaceutically acceptable acid addition salts by treating saidbase form with an appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The compounds of formulas (I), (II) and (III) which have acidicproperties may be converted in their pharmaceutically acceptable baseaddition salts by treating said acid form with a suitable organic orinorganic base. Appropriate base salt forms comprise, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. the benzathine, N-methyl-D-glucamine,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

The terms acid or base addition salt also comprise the hydrates and thesolvent addition forms which the compounds of formulas (I), (II) and(III) are able to form. Examples of such forms are e.g. hydrates,alcoholates and the like.

The term stereochemically isomeric forms of compounds of formulas (I),(II) and (III), as used hereinbefore, defines all possible compoundsmade up of the same atoms bonded by the same sequence of bonds buthaving different three-dimensional structures which are notinterchangeable, which the compounds of formulas (I), (II) and (III) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of a compound encompasses the mixture of all possiblestereochemically isomeric forms which said compound may possess. Saidmixture may contain all diastereomers and/or enantiomers of the basicmolecular structure of said compound. All stereo-chemically isomericforms of the compounds of formulas (I), (II) and (III) both in pure formor in admixture with each other are intended to be embraced within thescope of the present invention.

Some of the compounds of formulas (I), (II) and (III) may also exist intheir tautomeric forms. Such forms although not explicitly indicated inthe above formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term “compounds of formulas (I), (II) and(III)” is meant to include also the pharmaceutically acceptable acid orbase addition salts and all stereoisomeric forms.

Preferably the substituent R¹⁸ is situated on the 5 or 7 position of thequinolinone moiety and substituent R¹⁹ is situated on the 8 positionwhen R¹⁸ is on the 7-position.

Interesting compounds are these compounds of formula (I) wherein X isoxygen.

Also interesting compounds are these compounds of formula (I) whereinthe dotted line represents a bond, so as to form a double bond.

Another group of interesting compounds are those compounds of formula(I) wherein R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹,wherein Alk¹ is methylene and R⁹ is C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl.

Still another group of interesting compounds are those compounds offormula (I) wherein R³ is hydrogen or halo; and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy.

A further group of interesting compounds are those compounds of formula(I) wherein R² and R³ are on adjacent positions and taken together toform a bivalent radical of formula (a-1), (a-2) or (a-3).

A still further group of interesting compounds are those compounds offormula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen or C₁₋ ₆alkyl.

Yet another group of interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen; and R⁶ is C₁₋₆alkyl or halo,preferably chloro, especially 4-chloro.

A particular group of compounds are those compounds of formula (I)wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is hydrogen or C₁₋₆alkyl.

Preferred compounds are those compounds wherein R¹ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or aradical of formula —Alk¹—C(═O)—R⁹, wherein Alk¹ is methylene and R⁹ isC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl; R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy,hydroxyC₁₋₆alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to thenitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro;R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹ R¹² wherein R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is C₁₋₆alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.

Most preferred compounds are

4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-ethyl-2(1H)-quinolinone;

6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;

6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,

6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propyl-phenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salt; and in particular

(+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone(Compound 75 in Table 1 of the Experimental Part); or a pharmaceuticallyacceptable acid addition salt thereof.

Farnesyl protein transferase inhibitors can be formulated intopharmaceutical compositions as known in the art; for the compounds offormulas (I), (II) and (III) suitable examples can be found inWO-97/21701. To prepare the aforementioned pharmaceutical compositions,a therapeutically effective amount of the particular compound,optionally in addition salt form, as the active ingredient is combinedin intimate admixture with pharmaceutically acceptable carriers, whichmay take a wide variety of forms depending on the form of preparationdesired for administration.

These pharmaceutical compositions are, desirably as unitary dosageforms, administered orally, parenterally, percutaneously, rectally ortopically for systemic action, which is preferred, or for topicalaction. In case of oral liquid pharmaceutical preparations, comprisingsolutions, suspensions, syrups, elixirs and emulsions, any of the usualpharmaceutical media, such as, for example, water, glycols, oils,alcohols and the like, may be employed, whereas in case of oral solidpharmaceutical preparations, comprising powders, pills, capsules andtablets, excipients such as starches, sugars, kaolin, lubricants,binders, disintegrating agents and the like may be employed. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral unit dosage forms, in which case solid pharmaceuticalcarriers are obviously employed. In case of injectable pharmaceuticalcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, such as semipolair solvents,may be included, for example, to aid solubility. Examples of carriersfor injectable solutions comprise saline solution, glucose solution or amixture of saline and glucose solution. Injectable solutions containingcompounds of the aforementioned formulas may also be formulated in anoil for prolonged action. Appropriate oils for this purpose are, forexample, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil,synthetic glycerol esters of long chain fatty acids and mixtures ofthese and other oils. For the preparation of injectable suspensions,appropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wettable agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment or as a gel. In case of pharmaceuticalcompositions for rectal administration, any of the usual excipients maybe employed, comprising fat based and water soluble excipients,optionally combined with suitable additives, such as suspending orwetting agents. As appropriate compositions for topical applicationthere may be cited all compositions usually employed for topicallyadministering drugs e.g. creams, gellies, dressings, lotions, shampoos,tinctures, pastes, ointments, salves, ovules, powders, inhalations, nosesprays, eye drops and the like. Semisolid compositions such as salves,creams, gellies, ointments and the like will conveniently be used, butapplication of said compositions may be, for example, also by aerosol,e.g. with a propellent such as nitrogen, carbon dioxide, a freon, orwithout a propellent such as a pump spray or drops.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such unit dosage forms are tablets (includingscored or coated tablets), capsules, pills, powder packets,suppositories, ovules, wafers, injectable solutions or suspensions,teaspoonfuls, tablespoonfuls and the like, and segregated multiplesthereof.

Preferably, a therapeutically effective amount of the pharmaceuticalcomposition comprising a farnesyl protein transferase inhibitor isadministered orally or parenterally. Said therapeutically effectiveamount is the amount that effectively sensitizes a tumor in a host toirradiation. On the basis of the current data, it appears that thepharmaceutical composition comprising(+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(compound 75) as the active ingredient can be administered orally in anamount of from 10 up to 1500 mg/m² daily, either as a single dose orsubdivided into more than one dose, or more particularly in an amount offrom 100 to 1000 mg/m² daily.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumor by radionuclidescan be external or internal.

Preferably, the administration of the pharmaceutical compositioncommences up to one month, in particular up to 10 days or a week, beforethe irradiation of the tumor. Additionally, it is advantageous tofractionate the irradiation of the tumor and maintain the administrationof the pharmaceutical composition in the interval between the first andthe last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumor, its location, thepatients' reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumor comprising the steps of

administering a radiation-sensitizing effective amount of a farnesylprotein transferase inhibitor before, during or after

administering radiation to said host in the proximity to the tumor.

Examples of tumors which may be inhibited, but are not limited to, lungcancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), hematopoietic tumors of lymphoidlineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt'slymphoma), myeloid leukemias (for example, acute myelogenous leukemia(AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS),tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas),melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor ofthe skin (e.g. keratoacanthomas), breast carcinoma, kidney carninoma,ovary carcinoma, bladder carcinoma and epidermal carcinoma.

EXPERIMENTAL PART

The following tables show the formulas of the compounds of formula (I),their physical data, and references to the examples in WO-97/21701according to which the compounds in question may be prepared. In thepharmacological example, the radiation sensitizing effect of thecompounds of formula (I) is illustrated.

TABLE 1

Co. Ex. No. No. R¹ R^(4a) R⁸ Physical data  3 B.1 CH₃ CH₃ OH mp. 233.6°C.  4 B.3 CH₃ CH₃ OCH₃ mp. 140-160° C.; .C₂H₂O₄.H₂O  5 B.6 CH₃ CH₃ H mp.165° C.; .C₂H₂O₄.H₂O  6 B.5 CH₃ CH₂CH₃ H mp. 180° C.; .C₂H₂O₄.1/2H₂O  7B.2 H CH₃ H mp. 260° C.  8 B.2 H (CH₂)₃CH₃ OH —  9 B.4 CH₃ (CH₂)₃CH₃ OHmp. 174° C. 10 B.3 H CH₃ OCH₂COOC₂H₅ mp. 185° C.; .3/2C₂H₂O₄ 11 B.3 CH₃CH₃ O(CH₂)₂N(CH₃)₂ mp. 120° C. 12 B.7 CH₃ CH₃ CH₃ mp. 210° C.; .C₂H₂O₄13 B.7 CH₃ CH₃ CH₂CH₃ mp. 196° C.; .C₂H₂O₄ 14 B.13 CH₃ CH₃ NH₂ mp. 220°C. 72 B.13 CH₃ CH₃ NH₂ .3/2-(E)-C₄H₄O₄ 73 B.13 CH₃ CH₃ NH₂ .2HCl 74 B.8bCH₃ CH₃ NH₂ (A) 75 B.8b CH₃ CH₃ NH₂ (+) 15 B.3 CH₃ CH₃ O(CH₂)₃OH mp.135° C. 16 B.3 CH₃ CH₃ O(CH₂)₂CH₃ mp. 180° C.; .C₂H₂O₄.3/2(H₂O) 17 B.3CH₃ CH₃ O(CH₂)₂O—C₆H₅ mp. 144° C.; .3/2(C₂H₂O₄) 18 B.2 H CH(CH₃)₂ OH —19 B.4 CH₃ CH(CH₃)₂ OH mp. 254° C. 20 B.2 H (CH₂)₂OCH₃ OH mp. 112° C. 21B.4 CH₃ (CH₂)₂OCH₃ OH mp. 192° C. 22 B.3 CH₃ CH₃ O(CH₂)₂OH mp. 198° C.23 B.8a CH₃ CH₃ OH mp. 150-200° C.; (A); .C₂H₂O₄ 24 B.8a CH₃ CH₃ OH mp.150-200° C.; (B); .C₂H₂O₄ 25 B.11 CH₃ CH₃ CH₂—CN mp. 154° C. 27 B.2 H(CH₂)₃OCH₃ OH — 28 B.4 CH₃ (CH₂)₃OCH₃ OH mp. 196° C.; .H₂O 29 B.3 CH₃CH₃ O(CH₂)₃OCH₂CH₃ mp. 105° C.; .3/2(H₂O) 31 B.2 H CH₃ OH >260° C. 32B.6 CH₃ (CH₂)₂OCH₃ H mp. 140° C.; .3/2(C₂H₂O₄) 33 B.6 CH₃ (CH₂)₃OCH₃ Hmp. 180° C.; .HCl 56 B.12 CH₃ CH₃ —NHCOCH₃ .C₂H₂O₄ 58 B.11 CH₃ CH₃—CH₂COOCH₂CH₃ .C₂H₂O₄.3/2(H₂O) 60 B.11 CH₃ CH₃ 1-imidazolyl — 61 B.21CH₃ CH₃ —NH—CH₃ mp. 164° C. 65 B.2 H (CH₂)₃SOCH₃ OH .H₂O 66 B.13 CH₃ CH₃—N(CH₃)₂ .2C₂H₂O₄.H₂O mp. 160° C. 67 B.13 CH₃ CH₃ —NH—(CH₂)₂OCH₃ mp.216° C. 68 B.13 CH₃ CH₃ —NH—(CH₂)₂—OH — 69 B.7 CH₃ CH₃ —CH₂Cl .2C₂H₂O₄mp. 220° C. 70 B.7 CH₃ CH₃ —CH₂Br — 71 * CH₃ CH₃ —CH₂OH .2C₂H₂O₄ 76 B.4—(CH₂)₂OCH₃ CH₃ OH mp. 150° C. 77 * CH₃ CH₃ —CH₂OCH₃ .2C₂H₂O₄ mp. 166°C. 78 B.13 CH₃ CH₃ —NH—OCH₃ mp. 170° C. 79 B.20 CH₃ CH₃ —NH—CONH₂ .2H₂O80 ** CH₃ CH₃ —CH₂CONH₂ — 81 B.13 CH₃ CH₃ —NH—OH — 82 B.13 CH₃ CH₃—NH(CH₂)₂N(CH₃)₂ — .3/2C₂H₂O₄ 83 B.4 (CH₂)₂N(CH₃)₂ CH₃ OH .3/2H₂O mp.200 ° C. 84 * CH₃ CH₃ —CH₂N(CH₃)₂ .C₂H₂O₄ mp. 210° C. 85 B.4 CH₃ CH₃—N(CH₃)₂ — 86 B.4 CH₃ CH₃ NHCOCH₂N(CH₃)₂ — 87 B.4 CH₃ CH₃ —NH(CH₂)₉CH₃ —88 B.4 CH₃ CH₃ —NH(CH₂)₂NH₂ — 89 B.20 CH₃ CH₃ —NHCOCH₂OCH₃ .HCl mp. 220°C. 90 B.6 CH₃ CH₃ H — 91 B.20 CH₃ CH₃ —NHCOCH₂C₆H₅ .C₂H₂O₄.H₂O mp. 170°C. 92 B.20 CH₃ CH₃ —NHCOC₆H₅ mp. 242° C. 93 B.20 CH₃ CH₃ —NHCOCONH₂.C₂H₂O₄.H₂O mp. 186° C. 94 B.13 CH₃ CH₃ —NHC₆H₅ mp. 165° C. *: preparedby functional-group transformation of compound 70 **: prepared byfunctional-group transformation of compound 25

TABLE 2

Co. Ex. No. No. R¹ R² R^(4a) R⁵ R⁸ Physical data  1 B.1 CH₃ H CH₃ H OHmp. >250° C.  2 B.5 CH₃ H CH₃ H H mp. 100-110° C. 26 B.1 CH₃ 3-Cl CH₃2-CH₃ OH mp. 200° C. 30 B.6 CH₃ 3-Cl CH₃ 2-CH₃ H mp. 120-140° C.;.3/2(C₂H₂O₄).H₂O 34 B.1 CH₃ 3-O—CH₂—CH₃ CH₃ H OH mp. 190° C. 35 B.6 CH₃3-O—CH₂—CH₃ CH₃ H H mp. 160-180° C.; .HCl.H₂O 36 B.1 CH₃ 3-O—CH₃ CH₃ HOH mp. 210° C. 37 B.1 CH₃ 3-O—(CH₂)₂—CH₃ CH₃ H OH mp. 150-160° C. 38 B.1CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H OH mp. 150-160° C. 49 B.1 CH₃ 4-O—CH₂—CH₃ CH₃ HOH mp. 184.2° C. 50 B.1 CH₃ 3-O—CH—(CH₃)₂ CH₃ H OH mp. 147.1° C. 51 B.6CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H H mp. 164.2° C.; .3/2(C₂H₂O₄) 52 B.6 CH₃3-O—(CH₂)₂—CH₃ CH₃ H H .3/2(C₂H₂O₄) 53 B.6 CH₃ 3-O—CH—(CH₃)₂ CH₃ H H mp.133.9° C.; .C₂H₂O₄.H₂O 54 B.14 CH₃ 3-OH CH₃ H OH — 64 B.10 CH₃ 3-OH CH₃H OH .HCl.H₂O 55 B.6 CH₃ 3-OH CH₃ H H mp. >250° C. 57 B.1 CH₃ 2-OCH₂CH₃CH₃ H OH — 59 B.13 CH₃ 3-OCH₂CH₃ CH₃ H NH₂ — 95 B.8a CH₃ 3-OCH₂CH₃ CH₃ HNH₂ (A) 96 B.8a CH₃ 3-OCH₂CH₃ CH₃ H NH₂ (B) 62 B.15 CH₃ 3-O(CH₂)₂N(CH₃)₂CH₃ H OH — 63 B.11 CH₃ 3-O(CH₂)₂—OH CH₃ H OH — 97 B.1 CH₃ 3-CH₂CH₃ CH₃ HOH — 98 B.13 CH₃ 3-CH₂CH₃ CH₃ H NH₂ mp. 240° C. 99 B.1 CH₃ 3-(CH₂)₂CH₃CH₃ H OH — 100  B.13 CH₃ 3-(CH₂)₂CH₃ CH₃ H NH₂ — 101  * CH₃3-O—(CH₂)₂OCH₃ CH₃ H OH .3/2(C²⁻H₂O₄) mp. 193° C. 102  B.1 CH₃ 3-CH₃ CH₃H OH mp. >250° C. 103  B.13 CH₃ 3-CH₃ CH₃ H NH₂ — 104  B.1 CH₃ 3-Br CH₃H OH — 105  B.13 CH₃ 3-Br CH₃ H NH₂ — 106  B.1 CH₃ 3-O—CF₃ CH₃ H OH —107  B.13 CH₃ 3-O—CF₃ CH₃ H NH₂ mp. 168° C. 108  B.1 CH₃ 3-C₆H₅ CH₃ H OH— 109  B.13 CH₃ 3-C₆H₅ CH₃ H NH₂ — 110  B.1 CH₃ 3-F CH₃ H OH — 111  B.13CH₃ 3-F CH₃ H NH₂ mp. >250° C. 112  B.1 CH₃ 3-(E)-CH═CH—CH₃ CH₃ H OHmp. >250° C. 113  B.2 H 3-Cl CH₃ 3-Cl OH — 114  B.4 CH₃ 3-Cl CH₃ 3-Cl OH— 115  B.1 CH₃ 3-Cl H 3-CH₃ OH — 116  B.4 CH₃ 3-Cl CH₃ 3-CH₃ OH — 117 ** CH₃ 3-CN CH₃ H OH — 160  B.1 CH₃ 3-CF₃ CH₃ H OH — *: prepared byfunctional-group transformation of compound 54 **: prepared byfunctional-group transformation of compound 104

TABLE 3

Co. Ex. No. No. R¹ R⁸ Physical data 39 B.4 CH₂CONHCH(COOCH₃)(CH₂CH(CH₃)₂) H mp. 240° C. (S) 40 B.4 CH₂-2-quinolinyl H mp. 240° C.;.2 HCl 41 B.4 CH₂CONHCH(COOCH₃) (CH₂CH(CH₃)₂) OH mp. >260° C. (S)

TABLE 4

Co. Ex. No. No. R² R⁴ R^(5a) R⁶ R⁸ Physical data 42 B.6 H H H 4-Cl H mp.170° C.; .C₂H₂O₄.1/2 H₂O 43 B.10 H H H 4-Cl OH mp. 180° C.; .H₂O 44 B.5H H CH₃ 4-Cl H mp. 152° C. 45 B.6 3-Cl H H 4-Cl H mp. 175° C.; .C₂H₂O₄46 B.5 3-Cl H CH₂CH₃ 4-Cl H mp. 132° C.; .C₂H₂O₄ 47 B.5 3-Cl H CH₃ 4-ClH mp. 115° C.; .3/2 C₂H₂O₄ 48 B.9 3-Cl H CH₃ 4-Cl OH mp. 230° C. 118 B.4 3-Cl 3-CH₃ CH₃ 4-Cl OH mp. 222° C.

TABLE 5

Co. No. Ex. No. -R²-R³- R⁶ R⁸ 119 B.1 —O—CH₂—O— 4-Cl OH 120  B.13—O—CH₂—O— 4-Cl NH₂ 121 B.1 —O—CH₂—CH₂—O— 4-Cl OH 122  B.13 —O—CH₂—CH₂—O—4-Cl NH₂ 123 B.1 —O—CH═CH— 4-Cl OH

TABLE 6

Co. No. Ex. No. X

R² R³ R¹⁶ R⁸ Physical data 124 B.1 O double 3-OCH₃ 4-OCH₃ 5-OCH₃ OH mp.230° C. 125 B.13 O double 3-OCH₃ 4-OCH₃ 5-OCH₃ NH₂ mp. 218° C. .C₂H₂O₄126 B.1 O single 3-Cl H H OH mp. 160° C. 127 B.1 O single 3-Cl H H OH —128 B.16 S double 3-Cl H H H —

TABLE 7

Co. Ex. No. No. R¹ R¹⁷ R¹⁸ R¹⁹ R⁸ Physical data 129 B.17 H CN H H H —130 B.4 CH₃ CN H H H mp. 202° C. 131 B.17 H CN H H OH — 132 B.4 CH₃ CN HH OH — 133 B.17 H CN H H —CH₂CN — 134 B.4 CH₃ CN H H —CH₂CN mp. 138° C.135 B.18 H CH₃ H H OH — 136 B.4 CH₃ CH₃ H H OH — 137 B.13 CH₃ CH₃ H HNH₂ mp. >250° C. 138 B.18 H C₆H₅ H H H — 139 B.4 CH₃ C₆H₅ H H H.3/2(C₂H₂O₄) mp. 180° C. 140 B.18 H C₆H₅ H H OH — 141 B.4 CH₃ C₆H₅ H HOH — 142 B.13 CH₃ C₆H₅ H H NH₂ — 143 B.13 CH₃ Cl H H NH₂ — 144 B.17 H—COOCH₂CH₃ H H OH — 145 B.4 CH₃ —COOCH₂CH₃ H H OH — 146 B.1 CH₃ H 8-CH₃H OH — 147 B.13 CH₃ H 8-CH₃ H NH₂ .H₂O 148 B.1 CH₃ H 7-Cl H OH — 149 B.1CH₃ H 7-CH₃ H OH — 150 B.1 CH₃ H 5-CH₃ H OH — 151 B.1 CH₃ H 8-OCH₃ H OH— 161 B.1 CH₃ H 7-CH₃ 8-CH₃ OH mp. 255° C.

TABLE 8

Co. Ex. No. No. R² R³ R⁶ R⁷ R⁸ Physical data 152 B.1 3-OCH₂CH₃ H4-OCH₂CH₃ H OH .3/2(C₂H₂O₄) 153 B.1 3-Cl H H H OH — 154 B.1 3-Cl H 4-CH₃H OH — 155 B.1 3-Cl H 4-OCH₃ H OH — 156 B.1 3-Cl H 4-CF₃ H OH — 157 B.13-Cl H 2-Cl 4-Cl OH — 158 B.1 3-Cl 5-Cl 4-Cl H OH — 159 B.1

H 4-Cl H OH — 162 B.1 3-Cl H 4-S—CH₃ H OH mp. 169° C. .C₂H₂O₄.H₂O; 163B.1 3-Cl H 4-N(CH₃)₂ H OH mp. decompose s > 172° C. 164 B.1 3-Cl H—CH═CH—CH═CH— OH .C₂H₂O₄ * *: R⁶ and R⁷ taken together to form abivalent radical between positions 3 and 4 on the phenyl moiety

PHARMACOLOGICAL EXAMPLE 1

Male athymic nude mice weighing approximately 22 to 25 g were inoculatedsubcutaneously in the inguinal region with 1×10⁶ of LoVo human colontumor cells (LoVo cells) on day 0. After three weeks to allow tumors tobecome established (diameter approximately 0.5 to 1 cm), treatment wasstarted with solvent or compound 75 via the oral route, and either withor without a single shot irradiation on day 32. Parameters for activitywere tumor growth rate and weight of the tumors at day 42.

Compound 75 was dissolved in water and acidified with 1 N HCl solutionto pH 2.5 and administered orally (po) as 0.1 ml of compound solutionper 10 g mouse body weight twice daily (bid). The dose administered waseither 50 or 100 mg compound per kg bodyweight; treatment eitherpreceded irradiation (days 22-32), followed irradiation (days 32-42) orcontinued throughout the duration of the experiment (days 22-42).

Irradiation treatment consisted of a single dose of radiation on day 32with a dose of 7 Gy that stabilized tumor growth in untreated animals,i.e. a dose that stopped the increase in tumor volume, but did not causeany reduction in its size either.

The following table (Table 9) shows each of the arms that were evaluatedin the experiment. In each arm of the experiment 16 animals wereincluded. The column ‘tumor (g)’ contains the median of the tumor weightof the animals sacrificed at day 42 of the experiment. FIGS. 1 and 2represent the observed data in graphical form.

FIG. 1 shows the distribution of the tumor weights (g) of the testanimals receiving 50 mpk of test compound (po, bid).

FIG. 2 shows the distribution of the tumor weights (g) of the testanimals receiving 100 mpk of test compound (po, bid).

The gray box in the figures depicts the 25-75 percentiles, the solidblack line therein represents the median, the lines extending from thegray box depict the 10-90 percentiles and the black dots represent theoutliers. The Roman mumbers correspond to the groups of test animals asidentified in Table 9.

From a statistical analysis of the data it follows that treatment withcompound 75 (both 50 and 100 mpk) potentiates the effect of irradiation,more in particular that pretreatment with compound 75 (both 50 and 100mpk) and irradiation reduces tumor weight in a statistically significantmanner (when compared to irradiation alone).

TABLE 9 Compound Group 75 treatment schedule Irradiation tumor (g) Isolvent day 22-42 none 0.475 II  50 mpk day 22-42 none 0.255 III  50 mpkday 22-32 none 0.273 IV  50 mpk day 32-42 none 0.295 V 100 mpk day 22-42none 0.205 VI 100 mpk day 22-32 none 0.234 VII 100 mpk day 32-42 none0.277 VIII  50 mpk day 22-42 7 Gy 0.207 IX  50 mpk day 22-32 7 Gy 0.156(p = 0.03)* X  50 mpk day 32-42 7 Gy 0.259 XI 100 mpk day 22-42 7 Gy0.164 (p = 0.0317)* XII 100 mpk day 22-32 7 Gy 0.141 (p = 0.0022)* XIII100 mpk day 32-42 7 Gy 0.214 XIV Solvent day 22-42 7 Gy 0.256*Mann-Whitney U test vs Group XIV (radiotherapy only)

EXAMPLE 2

Radioresistant human glioma cell lines (SF763, U87, U251) were treatedwith compound 75, 48 h prior to irradiation (2 Gy). The doseadministered was 0.4 nM for U251 and 2 nM for SF763 and U87.

Applying compound 75 to the cells dramatically reduced the surviving ofthe cells after irradiation: for SF763 and U87, a decrease of survivingfraction of about 55% was demonstrated, whereas for U251, the decreasewas 25%.

These results demonstrate that treatment with compound 75 resensitizesradioresistant cells to irradiation.

What is claimed is:
 1. A method for sensitizing a tumor in a host toirradiation comprising the steps of: administering aradiation-sensitizing effective amount of a farnesyl protein transferaseinhibitor before, during or after irradiation; and administeringradiation to said host in the proximity to the tumor wherein saidfarnesyl protein transferase inhibitor is a compound of formula (I), ora compound of formula (II) or (III) which is metabolized in vivo to acompound of formula (I), said compounds being represented by:

or a steroisomeric form thereof, or a pharmaceutically acceptable acidor base addition salt thereof wherein in formula (I), (II), or (III) thedotted line represents an optional bond and wherein X is oxygen orsulfur; R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)R⁹ or—Alk¹—S(O)₂—R⁹, wherein Alk¹ is C₁₋₆alkanediyl, R⁹ is hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylaminosubstituted with C₁₋₆alkyloxycarbonyl, R², R³ and R¹⁶ each independentlyare hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, amino-C₁₋₆alkyloxy, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar2oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or when on adjacentpositions R² and R³ taken together may form a bivalent radical offormula —O—CH₂—O—  (a-1), —O—CH₂—CH₂—O—  (a-2), —O—CH═CH—  (a-3),—O—CH₂—CH₂—  (a-4), —O—CH₂—CH₂—CH₂—  (a-5), or —CH═CH—CH═CH—  (a-6); R⁴and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxy-C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ each independently are hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, Ar²oxy, trihalomethyl,C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when on adjacent positions R⁶ andR⁷ taken together may form a bivalent radical of formula—O—CH₂—O—  (c-1), or —CH═CH—CH═CH—  (c-2); R⁸ is hydrogen, C₁₋₆alkyl,cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, amino-carbonylC₁₋₆alkyl, or aradical of formula —O—R¹⁰  (b-1), —S—R¹⁰  (b-2), —N—R¹¹R¹²  (b-3),wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ orAr²C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, a natural amino acid, Ar¹carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxy-C₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical of formula —Alk²—OR¹³ or—Alk²—NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl;  R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl hydroxyC₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;  R¹⁴is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;  R¹⁵ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁷ is hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹; R¹⁸ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl; Ar¹ isphenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and Ar² is phenyl or phenyl substituted withC₁₋₆alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo.
 2. The method of claim1 wherein said farnesyl protein transferase inhibitor is a compound offormula (I) and wherein X is oxygen.
 3. The method of claim 1 whereinsaid farnesyl protein transferase inhibitor is a compound of formula (I)and wherein the dotted line represents a bond.
 4. The method of claim 1wherein said farnesyl protein transferase inhibitor is a compound offormula (I) and wherein R¹ is hydrogen, C₁₋₆alkyl,C₁₋₆alkyloxy-C₁₋₆alkyl or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl.
 5. Themethod of claim 1 wherein said farnesyl protein transferase inhibitor isa compound of formula (I) and wherein R³ is hydrogen and R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy orhydroxyC₁₋₆alkyloxy.
 6. The method of claim 1 wherein said farnesylprotein transferase inhibitor is a compound of formula (I) and whereinR⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,hydroxy, or a radical of formula —Alk²—OR¹³ wherein R¹³ is hydrogen orC₁₋₆alkyl.
 7. The method of claim 1 wherein the compound is selectedfrom the group consisting of:4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride monohydrate;6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,and6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salts thereof.
 8. The method of claim 1 wherein thecompound is(+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.
 9. Themethod of claim 1 wherein a radiation sensitizing amount of the farnesylprotein transferase inhibitor is administered orally, parenterally,rectally or topically.
 10. The method of claim 8 a pharmaceuticalcomposition comprising the compound is administered orally in an amountof from 10 to 1500 mg/m² of the compound, either as a single dose orsubdivided into more than one dose.
 11. The method of claim 1 whereinthe irradiation is ionizing irradiation.
 12. The method of claim 1wherein the irradiation of the tumor is external or internal.
 13. Themethod of claim 1 wherein the effective amount of the farnesyl proteintransferase inhibitor is part of a pharmaceutical composition comprisingat least the farnesyl protein transferase inhibitor.
 14. The method ofclaim 13 wherein the administration of the pharmaceutical compositioncommences up to one month before the irradiation of the tumor.
 15. Themethod of claim 1 wherein the irradiation of the tumor is fractionatedand the administration of the pharmaceutical composition is maintainedin the interval between the first and the last irradiation session.